EZH2 inhibition overcomes immune evasion in lung adenocarcinoma by restoring CCL5-mediated T-cell recruitment and MHC class I antigen presentation.

Immunotherapy represents a pivotal advancement in lung cancer treatment. However, its efficacy remains limited, necessitating a deeper understanding of intrinsic tumor cell mechanisms that modulate the immune microenvironment. Here, we investigate how EZH2 inhibition alters chemokine secretion and antigen presentation in lung adenocarcinoma (LUAD). TCGA and GEO analyses show significant overexpression of in LUAD, which correlates with poorer survival. Immune cell infiltration using MCP-Counter demonstrates that EZH2 expression inversely correlates with CD8 T cell and dendritic cell (DC) infiltration. Spatial analysis of early lung cancer samples reveals an inverse EZH2-CCL5 correlation, suggesting that EZH2 promotes progression via CCL5 suppression. assays included CCK-8 proliferation assays following EZH2 inhibition, qRT-PCR and ELISA to quantify CCL5 expression and secretion, transwell migration assays to assess CD8 T-cell chemotaxis, and co-culture cytotoxicity assays to evaluate MHC class I-dependent T-cell killing. Inhibition of EZH2 markedly reduces tumor cell proliferation, increases CCL5 expression and secretion, enhances CD8 T-cell migration, and promotes MHC class I expression and T-cell-mediated cytotoxicity without altering PD-L1 levels. In conclusion, overexpression promotes immune evasion in LUAD by suppressing CCL5-mediated T-cell recruitment and MHC class I antigen presentation. Targeting EZH2 augments antitumor immunity, supporting its therapeutic potential in combination immunotherapy strategies.